PROJECT SUMMARY/ABSTRACT Our long-term goal is to develop neurotechnologies that measure optical biomarkers indicative of early onset of Alzheimer?s Disease (AD) or treatment response. AD is a leading cause of adult disability and the most common cause of dementia in the United States. Despite the tremendous worldwide investment in addressing AD, therapeutic approaches shown to have efficacy in mouse models have failed in human clinical trials with late-onset sporadic AD. The overall objective of this application is to study the time course of cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) in development of late-onset sporadic AD pathology. We will address key issues such as age-related changes in cerebral microvascular structure (using optical clearing) and function (using optical measurements of CBF and CMRO2) applied to two AD mouse models: the well-established 3xTg model pioneered by co-I LaFerla, and the novel LaFerla hA?-KI model of LOAD pathogenesis. We propose use of three innovative concepts to study in vivo development of cerebrovascular dysfunction and development of AD pathology: 1) an animal model that recapitulates late-onset sporadic AD (LOAD pathogenesis, 2) a new in vivo optical imaging platform capable of absolute measurements of CBF and metabolism, and 3) ex vivo whole-brain visualization of brain structures with use of optical clearing and light-sheet microscopy. Our Specific Aims are to 1) Assess cross-sectional and longitudinal relationship among CBF, CMRO2, cerebrovascular pulsatility, and flow-metabolism coupling dynamics, in wild-type, 3xTg, and hA?-Ki mouse models; and 2) Validate vascular imaging biomarkers with microvascular structural parameters, neuroinflammation markers, and A?. Completion of these studies is expected to contribute to our knowledge on the relationship between neurovascular and metabolic alterations and AD pathogenesis. This innovative approach is expected to pave the way to enhanced understanding of age-related AD pathogenesis, and ultimately to informed development of new therapeutic strategies that target preservation of neurovascular health. We expect to establish a quantitative imaging platform that, due to its relatively low cost, can be readily utilized by other researchers worldwide